Parasitic Infections of the REVIEW ARTICLE

Nervous System

C O N T I N U UM A U D I O
INTERVIEW AVAILABLE
ONLINE
By Hector H. Garcia, MD, PhD

ABSTRACT
PURPOSE OF REVIEW: This article reviews how parasites affect the human
nervous system, with a focus on four parasitic infections of major public
health importance worldwide, two caused by protozoa (malaria and
toxoplasmosis) and two by helminths (neurocysticercosis and
schistosomiasis).
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RECENT FINDINGS:Parasitic infections in humans are common, and many can

affect the central nervous system where they may survive unnoticed or
may cause significant pathology that can even lead to the death of the
host. Neuroparasitoses should be considered in the differential diagnosis
of neurologic lesions, particularly in individuals from endemic regions or CITE AS:
CONTINUUM (MINNEAP MINN)
those with a history of travel to endemic regions. 2021;27(4, NEUROINFECTIOUS
DISEASE):943–962.

SUMMARY: Cerebral malaria is a significant cause of mortality, particularly in

Address correspondence to
African children, in whom infected red blood cells affect the cerebral
Dr Hector H. Garcia,
vessels, causing severe encephalopathy. Neurocysticercosis is the most Cysticercosis Unit, Instituto
common cause of acquired epilepsy worldwide and has varied clinical Nacional de Ciencias
Neurologicas, Jr. Ancash 1271,
presentations, depending on the number, size, and location of the Barrios Altos, Lima, Peru,
parasites in the nervous system as well as on the host’s inflammatory hgarcia@jhsph.edu.
response. Toxoplasmosis is distributed worldwide, affecting a significant
RELATIONSHIP DISCLOSURE:
proportion of the population, and may reactivate in patients who are Dr Garcia has served as an
immunosuppressed, causing encephalitis and focal abscesses. associate editor for the
Schistosomiasis causes granulomatous lesions in the brain or the American Journal of Tropical
Medicine and Hygiene and
spinal cord. PLOS Neglected Tropical
Diseases and as a board
member of the Oxfendazole
Development Group and has
received research grants from
INTRODUCTION the Fogarty International Center

A
parasite is an organism that lives on or in another organism from a (D43TW001140), National
different species, taking its nourishment from the host. Parasites do Institute of Allergy and
Infectious Disease
not always harm the host, and a typical vertebrate is the host of (U19AI129909), and National
many species of parasites. The human nervous system can be Institute of Neurological
Disorders and Stroke
invaded by multiple parasite species, which, in some cases, cause a
(U01NS086974).
significant burden of morbidity and mortality.
Endoparasites (those living inside the host) are classified as protozoa or UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
helminths. Protozoa are unicellular microscopic species, whereas helminths are USE DISCLOSURE:
more complex organisms and may reach several meters in length. Some parasites Dr Garcia reports no disclosure.
(such as Toxoplasma gondii or Toxocara canis) are distributed worldwide,
whereas others (such as Plasmodium, Schistosoma, and Taenia solium) occur in © 2021 American Academy
particular endemic regions but may be diagnosed in nonendemic areas because of of Neurology.

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

travel and migration of infected individuals.1 This article reviews how parasites
affect the human nervous system and the types of pathology they cause, focusing
on four parasitic infections of major public health importance worldwide, two
caused by protozoa (malaria and toxoplasmosis) and two by helminths
(neurocysticercosis and schistosomiasis). Other parasitic infections that can
rarely be seen in neurologic practice are also briefly discussed.

MECHANISMS OF PARASITE INVASION AND PATHOLOGY

Parasites use multiple mechanisms to overcome the physical and immunologic
barriers that vertebrates have evolved to protect their nervous systems. Some
parasites, such as free-living amoebas, can enter the central nervous system
(CNS) via the olfactory nerve.2 Others, such as most nematodes and cestodes,
enter the host via the bloodstream and thus require prior successful breaching
of the skin or mucosa3 either by the bite of a vector organism or secretion of
proteolytic enzymes. To enter the CNS, parasites must then traverse the blood-
brain barrier via a paracellular or transcellular route from the bloodstream or by
being transported in a macrophagic cell.3 Once the parasite enters the host, the
host immune system will attempt to destroy it; the parasite will try to avoid
destruction using mechanisms such as molecular mimicry, invasion of host cells,
and secretion of agents able to modulate the host immune response.
Entry of a parasite into the CNS does not necessarily mean CNS damage,
although, in most cases, it does result in pathology. CNS damage by parasites may
occur in diverse forms. Tissue damage may result from the presence of the
parasite, parasite products (ie, parasite proteases), or the host inflammatory
response to these products, for example, to dying and degenerating T. solium
cysts in neurocysticercosis. Larval and adult nematodes or cestodes may also
cause pathology by actively migrating through the host tissues, as in Gnathostoma
infections or other eosinophilic meningitis.
CNS parasitoses can result in a variety of lesions, including granulomatous or
cystic lesions, abscesses, encephalitis, meningitis, or myelitis, any of which may
occur alone or in combination. These can present with diverse clinical
manifestations, including seizures, focal deficits, mass effect, and intracranial
hypertension, and can also cause complications such as vasculitis, stroke, and
hydrocephalus.4

CEREBRAL MALARIA
Malaria is the most common parasitic disease of humans and the most common
parasitic cause of mortality and morbidity worldwide. Annually, malaria causes
more than 400,000 deaths in endemic regions, mostly in African children.5
Although it is usually considered a “tropical” disease, it is not restricted to the
tropics, and approximately 10,000 cases are diagnosed every year in travelers.6
Although four species of Plasmodium can cause human malaria, only Plasmodium
falciparum affects the CNS, resulting in the most severe form of disease, cerebral
malaria. Cerebral malaria may be the most common cause of nontraumatic
encephalopathy in the world.6,7

Life Cycle
Transmission of P. falciparum to humans occurs through the bite of an infected
Anopheles species mosquito. The parasite has a very complex life cycle. After
being injected under the skin, the infective sporozoites reach the liver and infect

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hepatocytes. In hepatocytes, they reproduce to significant numbers to form a KEY POINTS
hepatic schizont, after which the cell breaks and releases merozoites. Merozoites
● The human nervous
infect red blood cells and alter their shape and function. In the red blood cell, the system can be invaded by
parasites (now in the trophozoite stage) reproduce again to form schizonts and multiple parasite species,
rupture the erythrocyte, releasing a new generation of merozoites that infect new which, in some cases, cause
erythrocytes and continue the blood cycle. Synchronization of this blood cycle a significant burden of
morbidity and mortality.
and erythrocyte rupture causes the characteristic cyclical fever and malaise
(FIGURE 6-18). ● Parasites use multiple
mechanisms to overcome
Clinical Presentation the physical and
Severe malaria is defined by one or more of the following: impaired consciousness, immunologic barriers that
vertebrates have evolved to
prostration, multiple seizures, acidotic breathing, acute pulmonary edema and protect their nervous
acute respiratory distress syndrome, circulatory collapse or shock, low systolic systems.
blood pressure, acute kidney injury, clinical jaundice plus evidence of other vital
organ dysfunction, or abnormal bleeding.9,10 Cerebral malaria and severe malarial ● Malaria is the most
common parasitic disease of
anemia are the major causes of mortality in severe malaria. Cerebral malaria humans and the most
primarily affects children and nonimmune adults (such as travelers to endemic common parasitic cause of
regions). In children, cerebral malaria manifests as a febrile encephalopathy with mortality and morbidity
seizures (in more than 70%), with the usual case definition involving coma worldwide. Annually,
malaria causes more than
associated with acute infection with P. falciparum in the absence of other
400,000 deaths in endemic
identifiable causes.6 The most vulnerable age group is between 6 months and regions, mostly in African
children.

FIGURE 6-1
Life cycle of the malaria parasite.
Modified from JHSPH Open Courseware.8 © 2021 Johns Hopkins Bloomberg School of Public Health.

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

5 years old (other age groups are protected by maternal immunity or previous
exposure to the parasite). In the initial days of infection, nonspecific symptoms
develop (eg, fever, cough, and vomiting), with the child subsequently falling into
a deep coma with associated seizures. In adults, the progression to coma is gradual,
seizures are less frequently observed (in 15% to 20%), and multiorgan system
failure develops.11
Untreated cerebral malaria is lethal in all cases. Even under appropriate care,
short-term mortality may approach 15% to 30%. Approximately 30% of survivors
of cerebral malaria develop neurologic complications, such as epilepsy, cognitive
and behavioral disorders, or neurologic deficits.12,13 Adult survivors generally have
fewer neurologic complications but can rarely develop postmalaria neurologic
syndrome, which is similar to acute disseminated encephalomyelitis (ADEM).
Although the disease is called cerebral malaria, the parasite never invades the
brain tissues. The pathogenesis is not completely understood, but the principal
factor is the obstruction of blood vessels caused by intravascular sequestration of
infected red blood cells, with subsequent cytokine release, blood-brain barrier
disruption, brain edema, and metabolic alterations (FIGURE 6-214).6,15,16

Diagnosis
The diagnosis of malaria is based on the demonstration of parasite forms on blood
microscopy. However, a significant proportion of people in endemic regions
have asymptomatic parasitemia, and thus, the coexistence of parasitemia and
neurologic disease may be falsely diagnosed as cerebral malaria. Detection of
malaria retinopathy is highly sensitive (95%) and specific (90%) in identifying
children whose comas are due to cerebral malaria; therefore, funduscopy should
be performed in all suspected cases to look for retinal whitening, retinal
hemorrhages, papilledema, and vascular changes (FIGURE 6-3).10 CSF examination
is usually normal but helps to exclude other causes of encephalopathy, such as
bacterial meningitis in cases with increased CSF white blood cell counts.17 Lumbar
puncture does not increase the risk of mortality in clinically stable patients with
cerebral malaria despite evidence of brain edema.18 MRI can demonstrate increased
brain volume as well as abnormal T2 signal intensity and diffusion-weighted

FIGURE 6-2
Pathology of cerebral malaria. A, Macroscopic pathology of cerebral malaria (right)
compared to a normal brain (left). B, Close-up view of the brain demonstrating the typical
“flea-bitten” appearance resulting from multiple ring hemorrhages in the white matter.
Reprinted with permission from Román GC, J Neurol Sci.14 © 1991 Elsevier Inc.

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 KEY POINTS

● Untreated cerebral
malaria is lethal in all cases.
Even under appropriate
care, short-term mortality
may approach 15% to 30%.

● Up to one-third of the
world’s population is
infected with latent
toxoplasmosis (usually
asymptomatic), and disease
FIGURE 6-3 occurs when latent brain
Malarial retinopathy in pediatric patients from Malawi showing white-centered hemorrhages infections are reactivated in
(A), vessel discoloration (B), and perimacular whitening (C, circle). patients who become
Reprinted with permission from Taylor TT and Molyneux ME, Ann NY Acad Sci.11 © 2015 New York Academy of
immunocompromised.
Sciences.

imaging abnormalities in the cortical, deep gray, and white matter structures.19
Unfortunately, the availability of MRI is limited in malaria-endemic regions.

Treatment
Treatment of cerebral malaria requires IV antimalarials, with artesunate performing
better than quinine.10,20 Side effects of artesunate are infrequent, although delayed
hemolysis may occur a week after treatment.15 Seizures are usually managed with
phenobarbital and benzodiazepines, with respiratory suppression a common
complication. Enteral levetiracetam may provide an effective and safe alternative,21
although availability is limited in endemic areas. Otherwise, treatment is supportive,
with patients often requiring intensive care unit–level care.

TOXOPLASMOSIS
Toxoplasmosis is seen worldwide and is likely the most common parasitic infection of
the human CNS. Up to one-third of the world’s population is infected with latent
toxoplasmosis (usually asymptomatic), and disease occurs when latent brain infections
are reactivated in patients who become immunocompromised. Toxoplasmosis is the
most common opportunistic infection in patients with human immunodeficiency virus
(HIV), with highest risk when CD4+ counts are less than 100 cells/mm3.22,23

Life Cycle
Toxoplasmosis infection is caused by the ingestion of the tissue cysts or oocysts of
T. gondii in contaminated food or water. Cats are definitive hosts for Toxoplasma.
Oocysts are shed in the cat’s stools but are not infectious immediately (they
become infectious 1 to 5 days after being shed). Considering the risks of primary
nfections during pregnancy, it is recommended that pregnant women do not clean
litter boxes to avoid exposure. Primary infections in other immunocompetent
individuals are usually asymptomatic. In low-income countries, the majority of the
population has specific antibodies, compared to 10% to 50% of the population in
high-income countries.24,25 Before the antiretroviral treatment era, toxoplasmosis
reactivation rates in the United States and United Kingdom varied between 16%
and 40%, whereas in Brazil, France, and Spain, rates were even higher. Although
neurotoxoplasmosis is still a frequent cause of morbidity and mortality among

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

patients infected with HIV, especially in lower-income countries, mortality has

decreased substantially since the introduction of antiretroviral therapy.26

Clinical Presentation
The clinical manifestations of cerebral toxoplasmosis are usually subacute and
depend on the topography and number of lesions. The main symptoms are fever,

CASE 6-1 A 49-year-old man presented with a generalized seizure after a week
of headache. He reported a history of weight loss in the past 3 months.
On examination, the patient had normal mental status but left
hemiparesis with left-sided hyperreflexia.
Contrast-enhanced brain CT revealed three low-attenuation
parenchymal lesions. The largest lesion was in the right basal ganglia
associated with perilesional edema (FIGURE 6-4A). The results of a serum
enzyme-linked immunosorbent assay (ELISA) and Western blot for human
immunodeficiency virus (HIV)
were positive. Serum
ELISA for Toxoplasma
gondii was positive, and
the CD4+ count was
84 cells/mm3. Trimethoprim-
sulfamethoxazole,
dexamethasone, and
valproic acid were
initiated. After 2 weeks of
treatment, the patient had
complete neurologic FIGURE 6-4
recovery and showed Imaging of the patient in CASE 6-1. Axial CT shows a
partial resolution of his large rim-enhancing lesion in the right basal
ganglia associated with perilesional edema and
lesion burden on brain CT
midline shift (A) with marked improvement seen
(FIGURE 6-4B); antiretroviral after 2 weeks of anti-Toxoplasma treatment (B).
therapy was started. Images courtesy of Jose Vidal, MD.

COMMENT Cerebral toxoplasmosis is the most common cause of expansile brain

lesions in people living with HIV/acquired immunodeficiency syndrome
(AIDS) and continues to cause high morbidity and mortality in individuals
who are severely immunosuppressed. The most common characteristics
are focal subacute neurologic deficits and ring-enhancing brain lesions in
the basal ganglia, but the spectrum of clinical and neuroradiologic
manifestations is broad. Early initiation of anti-Toxoplasma therapy defines
the outcome. Trimethoprim-sulfamethoxazole and pyrimethamine-based
regimens seem to have similar efficacy, but trimethoprim-
sulfamethoxazole shows potential practical advantages. Most experts wait
for approximately 2 weeks after initiation of antiparasitic therapy before
starting antiretroviral therapy in this setting to decrease the risk of immune
reconstitution inflammatory syndrome.

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headache, seizures, focal deficits, confusion, lethargy, and visual alterations KEY POINT
related to retinal toxoplasmosis. Less frequent symptoms can include persistent
● The clinical
cognitive impairment and movement disorders.1 manifestations of cerebral
toxoplasmosis are usually
Diagnosis subacute and depend on the
On neuroimaging, cerebral Toxoplasma lesions can be unifocal or multifocal and topography and number of
lesions. The main symptoms
are most commonly located in the basal ganglia or subcortical white matter. On are fever, headache,
CT, they usually appear as hypodense ring-enhancing lesions with significant seizures, focal deficits,
perilesional edema (CASE 6-1), whereas on MRI they appear as T1-hypointense, confusion, lethargy, and
T2-hyperintense lesions with ring enhancement. These lesions may have small visual alterations related to
retinal toxoplasmosis.
hemorrhagic foci, or, more rarely, toxoplasmosis may present as an isolated
single or multiple cerebral hemorrhagic lesions. Two radiologic signs are highly
specific for the diagnosis. One is the eccentric target sign (a ring-shaped zone of
peripheral enhancement with a small eccentric nodule along the wall, observed
in <30% of cases)(FIGURE 6-527,28), and the other is the concentric target sign
(concentric alternating zones of hypointensity and hyperintensity seen on
T2-weighted MRI).29 These need to be distinguished from the target sign, which
has been described as a central nidus of calcification or central enhancement
surrounded by a ring of enhancement and is considered characteristic of CNS
tuberculoma.
Given the frequency of toxoplasmosis in the general population, a positive
IgG serology does not confirm the diagnosis. Acutely rising serum IgG
antibodies or a positive IgM serology suggests acute infection. IgM serology is
less specific as it may cross-react with other protozoa and may be positive in
patients with autoimmune disease. Negative serology in a patient with HIV
makes the diagnosis of toxoplasmosis unlikely. However, negative serology
does not exclude the diagnosis, especially in the presence of compatible clinical
and radiologic findings. Negative serology may represent a low titer below
the test cutoff and so does not exclude latent infection and risk of reactivation
in the setting of immune reconstitution; this is not common and occurs in
about 5% of cases. CSF polymerase chain reaction (PCR) is a useful tool for
diagnosis of T. gondii, with specificity between 96% and 100%. However, lumbar

FIGURE 6-5
Eccentric target sign. The eccentric target sign (A, arrow) in neurotoxoplasmosis shown in
coronal postcontrast T1-weighted MRI (A) and the target sign caused by tuberculoma shown
in axial CT before (B) and after (C) contrast.
Panel A reprinted with permission from Kumar GG, et al, J Magn Reson Imaging.27 © 2010 Wiley-Liss, Inc.
Panels B and C reprinted with permission from Van Dyk A, Neuroradiology.28 © 1988 Springer Nature.

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

puncture is not advisable for patients with cerebral lesions with significant
edema.30,31
The diagnosis of toxoplasmosis is usually confirmed with a favorable response
to anti-Toxoplasma treatment. Within 14 days of specific treatment, a good
clinical and neuroimaging response is expected. If patients do not respond to
therapy, a biopsy of the lesion is indicated to look for an alternative diagnosis,
although nuclear imaging studies (eg, positron emission tomography [PET] or
single-photon emission computed tomography [SPECT]) may be considered to
differentiate toxoplasmosis from primary CNS lymphoma.
The most common differential diagnosis of neurotoxoplasmosis in
lower-income countries is tuberculoma, whereas in higher-income countries
primary CNS lymphoma should be considered. In patients infected with HIV,
other infections, such as cryptococcosis, aspergillosis, microsporidiosis, and
Chagas disease, should also be considered in the differential diagnosis of single or
multifocal brain lesions.23 Individuals who are immunocompetent may very
rarely develop neurotoxoplasmosis, mostly as an acute diffuse encephalitis due to
overwhelming primary infection. This is extremely rare, and such patients
should be carefully evaluated for undiagnosed immunodeficiency.

Treatment
Therapy with pyrimethamine-based treatment or trimethoprim-sulfamethoxazole is
usually effective, with clinical and radiologic improvement in 80% to 90%
of patients receiving one of these regimens. In patients with sulfa allergy,
either clindamycin or atovaquone can be used in combination with
pyrimethamine. Treatment is continued for at least 6 weeks; if immunosuppression
is present, secondary prophylaxis with trimethoprim-sulfamethoxazole or
pyrimethamine-sulfadiazine is continued indefinitely. Recent data suggest that
trimethoprim-sulfamethoxazole can be used for primary therapy in place of
pyrimethamine-sulfadiazine with good outcomes.22 Potential advantages of
trimethoprim-sulfamethoxazole over pyrimethamine-based protocols include lower
pill burden and less-frequent dosing, the availability of IV formulations (important
for patients who are critically ill), the availability of multiple generic formulations
with the consequent impact on cost, and increased accessibility in poor regions.
Additionally, trimethoprim-sulfamethoxazole prevents Pneumocystis jirovecii
pneumonia, other bacterial infections, and malaria and simplifies the early initiation
of combination antiretroviral therapy. Steroids may be useful if the lesions have
mass effect or when diffuse or significant cerebral edema is seen.22,32

NEUROCYSTICERCOSIS
Cysticercosis is the most common helminthic infection of the CNS, affecting
patients in not only lower-income countries but also higher-income countries
because of migration and travel. Neurocysticercosis represents a significant cause
of morbidity and mortality, causing approximately 30% of cases of epilepsy in
endemic regions,33-35 making it the most common preventable risk factor for
acquired epilepsy in adults.13

Life Cycle
Cysticercosis is caused by the cystic larval form of the pork tapeworm T. solium,
the life cycle of which involves pigs as the usual intermediate host (cysticercosis,
larval infection) and humans as the sole definitive host, harboring the adult

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tapeworm in the small intestine when acquired from eating undercooked pork KEY POINTS
(taeniasis). Humans develop neurocysticercosis when ingesting the eggs of the
● Therapy with
tapeworm via fecal-oral transmission. Although the immune response of the host pyrimethamine-based
works to destroy the infective embryos that are distributed in diverse tissues, treatment or trimethoprim-
cysticerci have developed a series of immune evasion mechanisms, including sulfamethoxazole is
localizing in protected sites (such as the cerebral parenchyma, protected by the usually effective for
neurotoxoplasmosis, with
blood-brain barrier), secreting molecules able to block the complement system,
clinical and radiologic
affecting the cellular response, degrading attacking immunoglobulins, or even improvement in 80% to 90%
covering themselves with host immunoglobulins. Established cysts may survive of patients receiving one of
for years or even decades in the human brain, but they eventually begin to these regimens.
degrade, losing their ability to evade the host’s immune response. The evolution
● Neurocysticercosis
of the cyst goes from a quiescent viable state to a degenerating cyst and then to represents a significant
complete resolution or calcification, generating focal inflammation throughout source of morbidity and
the process.36,37 mortality, causing
approximately 30% of cases
of epilepsy in endemic
Clinical Presentation regions, making it the most
Neurocysticercosis varies in clinical and radiologic presentation depending on the common preventable risk
location, size, and number of lesions and host immune response (FIGURE 6-638). factor in the world for adult
Seizures and headaches are the most common symptoms in neurocysticercosis and acquired epilepsy.
may occur with parenchymal cysts in any stage (CASE 6-2). Extraparenchymal cysts
● Neurocysticercosis varies
in the cerebral ventricles or in the subarachnoid spaces (racemose cysts) can cause in clinical and radiologic
mass effect, hydrocephalus, intracranial hypertension, and chronic arachnoiditis presentation depending on
(CASE 6-3)39 and are associated with a poorer prognosis.33 Spinal cord cysticercosis the location, size, and
number of lesions and host
occurs less commonly but may be an underrecognized cause of myelopathy in
immune response.
endemic regions because of limited access to neuroimaging. Asymptomatic
involvement of the muscle and subcutaneous tissue also occurs.

Diagnosis
The diagnosis of neurocysticercosis is based on neuroimaging and is supported
by immunodiagnostic tests.40 Neuroimaging is key for the diagnosis and
provides data on the number, size, localization, and stage of lesions as well as
perilesional inflammation. Guidelines published by the Infectious Disease
Society of America and the American Society of Tropical Medicine and Hygiene
for the diagnosis of neurocysticercosis recommend that patients should be
assessed with both CT and MRI.41 Brain CT provides clinicians the capacity to
visualize lesions in the brain parenchyma, and MRI represents a more sensitive
technique that improves imaging definition for parenchymal lesions and
sensitivity for extraparenchymal lesions, although its sensitivity to detect
calcified lesions is limited. Parenchymal cysts go through a series of evolutive
(involutive) stages, beginning with a viable, noninflamed cyst (vesicular stage)
that later demonstrates degenerative changes, including increased density of its
fluid contents (colloidal stage), local inflammation with edema, and contrast
enhancement, and ultimately collapse into an inflammatory nodule (granular-
nodular stage) and disappear, followed by subsequent reappearance as a calcified
scar (nodular calcified stage) in 30% to 40% of cases. The tapeworm head
(scolex) is frequently seen as an eccentric nodule in the interior of the cyst.
Rarely, some patients (particularly young women) may present with hundreds
or thousands of cysts with a diffuse inflammatory reaction and brain edema, a
condition called cysticercotic encephalitis. Subarachnoid lesions frequently grow
and infiltrate neighboring spaces; uncontrolled growth of the parasitic

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

FIGURE 6-6
Types and stages of neurocysticercosis. A, Axial T1-weighted MRI shows multiple viable
parenchymal cysts. B, Axial postcontrast T1-weighted MRI shows a large occipital cyst with
contrast enhancement. C, Sagittal postcontrast T1-weighted MRI shows an enhancing lesion
with contrast enhancement and edema. D, Axial noncontrast CT shows multiple parenchymal
calcifications. E, Axial fluid-attenuated inversion recovery (FLAIR) MRI shows cysticercotic
encephalitis. F, Axial FLAIR MRI shows a cyst in the left lateral ventricle. G, Axial postcontrast
CT shows subarachnoid neurocysticercosis of the sylvian fissure. H, Axial T1-weighted MRI
shows subarachnoid neurocysticercosis in the basal cisterns.
Modified with permission from García HH, et al, Clin Microbiol Rev.38 © 2002 American Society for
Microbiology.

membrane in subarachnoid neurocysticercosis leads to large parasite clusters that

resemble a bunch of grapes called racemose neurocysticercosis (FIGURE 6-6H).
Routine hematologic tests are mostly noncontributory, and eosinophilia is
infrequent. CSF cellularity and biochemistry findings are also nonspecific,
including moderate pleocytosis with lymphomononuclear predominance,
increased protein, and, in severe cases, low glucose.
When neuroimaging tests are not conclusive, specific serology plays a major
role in confirming the diagnosis. Antibody detection is frequently used because
of its higher sensitivity, whereas antigen detection provides information on the
presence of living parasites. The enzyme-linked immunoelectrotransfer blot
(EITB) assay using lentil-lectin purified glycoprotein parasitic antigens in serum
is the assay of choice for antibody detection, with 98% sensitivity in those with
more than one live brain cyst and a specificity close to 100%. In patients with a
single brain cyst, the sensitivity drops and may be as low as 70%. No advantage is
seen in using CSF for EITB antibody detection. The viability of the lesion is a
major factor affecting antibody responses. Antigen detection is less sensitive than
antibody detection on EITB, but when it is positive, it confirms the presence of
living parasites and helps monitor the efficacy of antiparasitic treatment.42,43

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 A 25-year-old man presented because of an episode that occurred CASE 6-2
while he was teaching a class when he developed sudden loss of
consciousness, fell to the ground, and developed a rigid posture
followed by involuntary movements of all four limbs for approximately
3 minutes. After the episode, he regained consciousness but was still
drowsy when brought to the emergency department. He had a 2-year
history of sporadic episodes of visualization of multiple colored lights
followed by headache. He lived in a major city in Peru and rarely traveled;
however, his family from the highlands regularly visited and stayed at
his house.
On examination, he was awake and oriented in time, place, and person.
He had a bite wound on his tongue. He had generalized muscle
weakness but no focal findings or any other neurologic finding.
Brain MRI showed one
left occipital cystic lesion
with surrounding edema
(FIGURE 6-7A). Two additional
cystic lesions without edema
were also observed,
suggesting cysticercosis cysts
and scoleces (FIGURE 6-7B).
Serum enzyme-linked
immunoelectrotransfer blot
(EITB) assay for Taenia solium
was positive. Levetiracetam FIGURE 6-7
Imaging of the patient in CASE 6-2. A, Coronal
was started, and after a few T2-weighted MRI shows a cortical cystic lesion
days, a 2-week course of with surrounding edema in the left occipital lobe.
albendazole and praziquantel B, Axial fast imaging employing steady state
with concomitant acquisition (FIESTA) MRI demonstrates two
additional cysts, one juxtacortically in the right
dexamethasone was initiated. frontal lobe and another near the convexity, both
Over 2 years of follow-up, no with a hyperintense liquid content and a central
relapses occurred. hypointense scolex.

Intraparenchymal neurocysticercosis is a common cause of adult-onset COMMENT

epilepsy in endemic regions. EITB is highly sensitive in patients with more
than one cyst. Cases in urban areas outside endemic regions are not
uncommon because of the high influx of migration and complex population
dynamics. After infection, patients are usually asymptomatic for long
periods of time before presenting with symptoms, and symptoms
frequently occur at the time one or more of the cysts begin to degenerate
because of local inflammation. Corticosteroids are recommended along
with antiparasitic treatment to control inflammation and its complications.

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

CASE 6-3 A 55-year-old woman presented with a 1-year history of headaches that
partially improved with analgesics. One week earlier, the headache had
worsened, did not improve with oral analgesics, and was accompanied by
nausea and vomiting. On the morning of the day of admission, she was
somnolent and did not recognize her husband, so she was brought to the
hospital.
On examination, she was lethargic and disoriented with respect to
person, place, and time. She had no focal neurologic deficits, and her
vital signs were normal.
Initial brain CT showed ventriculomegaly with transependymal edema,
suggesting acute hydrocephalus. Ventriculoperitoneal shunt placement
was performed. The patient recovered, and follow-up MRI demonstrated
resolution of hydrocephalus but revealed anterior temporal,
pontocerebellar, and pontine
cystic mass subarachnoid
lesions (FIGURE 6-8).
Serum enzyme-linked
immunoelectrotransfer
blot (EITB) assay
for Taenia solium was
strongly positive. A
monoclonal antibody–
based enzyme-linked
immunosorbent assay (ELISA)
FIGURE 6-8
for circulating antigen
Imaging of the patient in CASE 6-3. A, Initial
was also strongly head CT reveals diffuse ventriculomegaly
positive. She received with transependymal edema. B, Axial fast
a 30-day course imaging employing steady state acquisition
(FIESTA) MRI reveals cystic lesions in the right
of albendazole and
perimesencephalic cistern and the left sylvian
dexamethasone with slow fissure. The lesions seen here are poorly defined
tapering of steroids. on CT.

COMMENT Subarachnoid neurocysticercosis can be life-threatening because of

intracranial hypertension with or without hydrocephalus by direct mass
effect or arachnoiditis, or both. Serology commonly shows very high
antigen levels and antibody responses. MRI is usually required for the
diagnosis because CT may only show enlarged or distorted ventricles or
subarachnoid spaces without a clear demonstration of parasitic lesions.
Management requires long-term antiparasitic treatment but may also
require surgical excision of large lesion conglomerates. Higher doses of
steroids help to reduce complications before, during, and following
antiparasitic treatment.

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 Standard diagnostic criteria for neurocysticercosis were first developed in 1996 KEY POINTS
and last updated in 2017 (TABLE 6-1)40,44; they include absolute (confirmatory
● The enzyme-linked
by itself ), neuroimaging, and clinical/exposure criteria, prioritizing neuroimaging immunoelectrotransfer blot
as the key tool for establishing the diagnosis.40 assay using lentil-lectin
purified glycoprotein
Treatment parasitic antigens in serum is
the assay of choice for
Therapy for neurocysticercosis includes treatment of seizures and elevated
antibody detection of
intracranial pressure, if present, and antiparasitic drugs (often with steroids) if viable neurocysticercosis.
or degenerating cysts are present. Based on studies in pigs and human pathology
samples, a cyst is considered viable if it has liquid contents, and these appear similar to ● For a single parenchymal
CSF on MRI (hypointense on T1-weighted and fluid-attenuated inversion recovery cyst in neurocysticercosis,
albendazole at 15 mg/kg/d
[FLAIR] sequences, hyperintense on T2-weighted images). Degenerating cysts may for 7 to 15 days is the
have lost their ability to produce an adult tapeworm, but these lesions still contain live regimen of choice. In cases
parasitic tissue and cells. After a long controversy regarding whether the use of with multiple viable cysts,
antiparasitic treatment was of benefit or whether it was unnecessary,45 most experts the combination of
albendazole plus
now agree that it destroys parasitic cysts and results in fewer seizure recurrences46,47; praziquantel at 50 mg/kg/d
therefore, it is of benefit in most patients with neurocysticercosis. Antiparasitic for 10 days has
treatment, however, may temporarily worsen neurologic symptoms because of demonstrated superior
the resulting inflammation around a damaged cyst. It is contraindicated in patients efficacy.
with uncontrolled elevated intracranial pressure and is usually administered with
● Schistosomal infection of
concomitant steroid therapy. For a single parenchymal cyst, albendazole at the central nervous system
15 mg/kg/d for 7 to 15 days is the regimen of choice. In cases with multiple viable (neuroschistosomiasis) is a
cysts, the combination of albendazole plus praziquantel at 50 mg/kg/d for 10 days rare complication of
schistosomiasis presenting
has demonstrated superior efficacy.41,46-49 Surgical management is limited to the
with myelopathy or
placement of ventriculoperitoneal shunts in patients with hydrocephalus and encephalopathy; it can
neuroendoscopic removal of intraventricular cysts, and occasionally large cysts or present months to years
cystic masses are surgically excised.50 after exposure.
Neurocysticercosis represents a significant burden worldwide and accounts for
tens of thousands of deaths per year. Significant advances have been achieved in
the past decade, including the demonstration that active interventions, such as
antiparasitic treatment of the human and porcine population as well as pig
vaccination, can interrupt transmission and lead to focal elimination.51 Larger
elimination efforts should demonstrate the feasibility of sustained elimination and
potential eradication.

SCHISTOSOMIASIS
Schistosomiasis is a chronic parasitic disease caused by trematode blood flukes of
the genus Schistosoma. It is endemic to sub-Saharan Africa, South America, the
Caribbean, Southwest Asia, and the Middle East.4,52,53 Three species of the
Schistosoma genus account for most cases of human schistosomiasis: Schistosoma
mansoni (Africa; Southeast Asia; and parts of Brazil, Venezuela, and the
Caribbean), Schistosoma haematobium (Africa, Southeast Asia, and the Middle
East), and Schistosoma japonicum (China, Indonesia, and the Philippines).1,17
Schistosomal infection of the CNS (neuroschistosomiasis) is a rare complication of
schistosomiasis presenting with myelopathy or encephalopathy; it can present
months to years after exposure.

Life Cycle
Humans are the definitive hosts for schistosomes. Infection occurs when the skin
of the individual is penetrated by cercariae, the free-swimming larval form of the

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

parasite, following exposure to fresh water infested with these parasites.52,53

Cercariae then migrate through capillaries and lymphatics to the portal venous
system, where they mature to adult worms over a few weeks. These then migrate
to the venous system of either the gastrointestinal tract (S. mansoni, S. japonicum)
or bladder (S. haematobium), and in 4 to 12 weeks, the adult parasites begin to
lay eggs, which typically lodge in the intestine or bladder mucosa and are shed in
the feces or urine, respectively. Neuroschistosomiasis is caused by ectopic
deposition of eggs in the brain and spinal cord by retrograde flow from the iliac
veins and inferior vena cava through the valveless Batson venous plexus
into the spinal cord. The eggs are immunogenic, and the host response leads to
granulomatous inflammation, with local edema, congestion, and varying degrees
of fibrosis.17,53 Cerebral schistosomiasis is more common with S. japonicum, as it has
smaller eggs that are able to migrate to the brain. The eggs of S. mansoni and

TABLE 6-1 Revised Diagnostic Criteria and Degrees of Diagnostic Certainty for
Neurocysticercosisa

Diagnostic criteria
◆ Absolute criteria
◇ Histologic demonstration of the parasite from biopsy of a brain or spinal cord lesion
◇ Visualization of subretinal cysticercus
◇ Conclusive demonstration of a scolex within a cystic lesion on neuroimaging studies
◆ Neuroimaging criteria
◇ Major neuroimaging criteria
→ Cystic lesions without a discernible scolex
→ Enhancing lesionsb
→ Multilobulated cystic lesions in the subarachnoid space
→ Typical parenchymal brain calcificationsb
◇ Confirmative neuroimaging criteria
→ Resolution of cystic lesions after cysticidal drug therapy
→ Spontaneous resolution of single small enhancing lesionsc
→ Migration of ventricular cysts documented on sequential neuroimaging studiesb
◇ Minor neuroimaging criteria
→ Obstructive hydrocephalus (symmetric or asymmetric) or abnormal enhancement of
basal leptomeninges
◆ Clinical/exposure criteria
◇ Major clinical/exposure
→ Detection of specific anticysticercal antibodies or cysticercal antigens by
well-standardized immunodiagnostic testsb
→ Cysticercosis outside the central nervous systemb
→ Evidence of a household contact with Taenia solium infection.

CONTINUED ON PAGE 957

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S. haematobium are larger and more frequently migrate to the lumbosacral spinal
cord, although they may occasionally affect the brain.1

Clinical Presentation
Acute cerebral neuroschistosomiasis may produce a nonspecific encephalopathy
that generally resolves within a few days or weeks. Chronic infection can present
as a slowly expanding intracranial mass (pseudotumor), which can be a solitary
mass or multiple mass lesions because of the development of parenchymal brain
granulomas.1,17,53 The most common manifestation of neuroschistosomiasis is
headache, and other symptoms vary depending on the location of the lesion in
the brain (motor deficits, visual abnormalities, seizures, altered mental status,
vertigo, sensory impairment, speech disturbances, cognitive impairment,
vomiting, and ataxia). Parenchymal brain and subarachnoid hemorrhages may

CONTINUED FROM PAGE 956

◇ Minor clinical/exposure
→ Clinical manifestations suggestive of neurocysticercosisb
→ Individuals coming from or living in an area where cysticercosis is endemicb
Degree of diagnostic certainty
◆ Definitive diagnosis
◇ One absolute criterion
◇ Two major neuroimaging criteria plus any clinical/exposure criteria
◇ One major and one confirmative neuroimaging criterion plus any clinical/exposure criteria
◇ One major neuroimaging criterion plus two clinical/exposure criteria (including at least one
major clinical/exposure criterion), together with the exclusion of other pathologies
producing similar neuroimaging findings
◆ Probable diagnosis
◇ One major neuroimaging criterion plus any two clinical/exposure criteria
◇ One minor neuroimaging criterion plus at least one major clinical/exposure criterion

a
Reprinted with permission from Del Brutto OH, et al, J Neurol Sci.44 © 1996 Elsevier Science B.V.
b
Operational definitions. Cystic lesions: rounded, well-defined lesions with liquid contents of signal similar
to that of CSF on CT or MRI; enhancing lesions: single or multiple, ring- or nodular-enhancing lesions of
10 mm to 20 mm in diameter, with or without surrounding edema, but not displacing midline structures;
typical parenchymal brain calcifications: single or multiple, solid, and most usually <10 mm in diameter;
migration of ventricular cyst: demonstration of a different location of ventricular cystic lesions on
sequential CTs or MRIs; well-standardized immunodiagnostic tests: so far, antibody detection by
enzyme-linked immunoelectrotransfer blot assay using lentil lectin-purified T. solium antigens, and
detection of cysticercal antigens by monoclonal antibody-based enzyme-linked immunosorbent assay
(ELISA); cysticercosis outside the central nervous system: demonstration of cysticerci from biopsy of
subcutaneous nodules, x-ray films or CT showing cigar-shaped calcifications in soft tissues, or visualization
of the parasite in the anterior chamber of the eye; suggestive clinical manifestations: mainly seizures
(often starting in individuals aged 20 to 49 years; the diagnosis of seizures in this context is not excluded if
patients are outside of the typical age range), but other manifestations include chronic headaches, focal
neurologic deficits, intracranial hypertension and cognitive decline; cysticercosis-endemic area:
a place where active transmission is documented.
c
The use of corticosteroids makes this criterion invalid.

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

KEY POINT
● Transverse myelitis is
the most common
presentation of spinal
neuroschistosomiasis and is
related to granulomatous
lesions with inflammatory
necrosis of the spinal cord.
occur in some cases and are related to segmental damage of small leptomeningeal
or parenchymal blood vessels induced by the parasites. Signs of systemic
schistosomiasis are typically absent.1,17,54,55
On CT and MRI, cerebral neuroschistosomiasis lesions appear as solitary or
multiple subcortical mass lesions surrounded by hypodense or T2-hyperintense
edema, with heterogeneous contrast enhancement and irregular borders. A linear
enhancement pattern surrounded by multiple enhancing nodules (the arborized
pattern) is suggestive but nonspecific for neuroschistosomiasis (FIGURE 6-9).1,2,4,53-57
Transverse myelitis is the most common presentation of spinal
neuroschistosomiasis and is related to granulomatous lesions with inflammatory
necrosis of the spinal cord. Symptoms usually progress in an acute to subacute time
course, with a peak at 15 days after the onset of symptoms. Granulomas may form in
the spinal cord, nerve roots, or, most commonly, both. The lower spinal cord is most
frequently affected, specifically at the levels of T11 through L1, possibly because of
increased anastomoses between the Batson venous plexus with the portal venous
system at this location.52,53,58 The most common initial symptoms are low back pain (in
79% to 100% of individuals) or pain in the lower limbs, which can be symmetric or
asymmetric. Lower spinal cord or cauda equina or conus medullaris involvement is
common, causing weakness of the lower limbs (CASE 6-4), lower limb sensory
disturbance, sphincter dysfunction, sexual dysfunction, and abnormal reflexes.1,53,58
In some patients, acute paraplegia may result from occlusion of the anterior spinal
artery by the parasites. CSF analysis usually reveals mild mononuclear pleocytosis and
an increased protein level. MRI typically reveals enlargement of the lower spinal cord
or the conus medullaris on T1-weighted images, signal hyperintensity on T2-weighted
images, and heterogeneous nerve root patterns of contrast enhancement.1,52,53
Neuroschistosomiasis should be suspected in patients who live in or traveled to an
endemic area and who present with a compatible clinical syndrome.

FIGURE 6-9
Axial postcontrast T1-weighted MRI
shows patchy enhancement in an
arborized pattern in the left temporal
lobe in cerebral schistosomiasis.
Reprinted with permission from Cho T,
Continuum (Minneap Minn).53 © 2018
American Academy of Neurology.
Diagnosis
Diagnosis requires evidence of active
Schistosoma infection. Direct visualization
of eggs in stool or urine, punch biopsy from
the rectal mucosa (higher sensitivity),52 or
indirect assays measuring antibodies against
schistosomal antigens have variable
sensitivity depending on the timing and
burden of infection. Serologic testing is
not useful in individuals from endemic
regions because schistosomiasis may cause
asymptomatic infection and schistosomal
antibodies may persist for years. Since the
radiographic pattern in cerebral
schistosomiasis is nonspecific, brain
biopsy may be required to confirm the
diagnosis.52,53
Treatment
Both cerebral and spinal cord
neuroschistosomiasis are managed almost
exclusively medically and only rarely

958 AUGUST 2021

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require surgical intervention (eg, decompressive laminectomy, mass excision,
liberation of roots for larger granulomas in spinal cord neuroschistosomiasis).
Praziquantel is effective in patients with brain or spinal cord involvement, but
dosing and timing lack evidence-based guidelines (recommended dose varies by
species).53,54 Some investigators have reported improved outcomes from
maximal surgical resection followed by praziquantel. Steroids should be initiated
if neuroschistosomiasis is suspected, followed by praziquantel once the diagnosis is
confirmed. Corticosteroids can mitigate the process of endarteritis, which can lead to
progressive brain and spinal cord damage. In general, the outcome tends to be worse
for spinal cord neuroschistosomiasis than cerebral neuroschistosomiasis.1,53

A 22-year-old man traveled to Malawi. Three months after returning to CASE 6-4
the United States, he noticed back pain and weakness in both legs that
progressively worsened. A spinal MRI demonstrated an intramedullary
lesion at the T11-T12 level (FIGURE 6-10A59). Serum laboratory evaluation
including comprehensive metabolic panel, liver function tests, and
complete blood cell count were normal, and no parasite eggs were found
in stools or urine. Surgery was performed, and pathologic examination of
the excised tissue revealed an inflammatory granuloma around a
crenated Schistosoma egg (FIGURE 6-10B). Postsurgical evolution was
favorable with complete recovery.

FIGURE 6-10
Imaging of the patient in CASE 6-4 with spinal schistosomiasis. A, Sagittal postcontrast
T1-weighted MRI of the spine shows an intramedullary lesion in the lower thoracic spine. B,
Pathologic (hematoxylin and eosin [H&E]) specimen from the same lesion shows a
granuloma around a Schistosoma egg.
Images courtesy of Christina Coyle, MD. Reprinted from Coyle CM, Handb Clin Neurol.59 © 2013 Elsevier B.V.

Spinal schistosomiasis should be suspected in travelers to endemic regions COMMENT

who develop compatible neurologic, particularly spinal, manifestations.
The finding of Schistosoma eggs in feces or urine establishes the diagnosis,
although the sensitivity of parasitologic diagnosis is limited.

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PARASITIC INFECTIONS OF THE NERVOUS SYSTEM

KEY POINT
● A variety of parasitic
infections may affect the
human central nervous
system less frequently.
Epidemiologic suspicion,
particularly in the settings of
atypical clinical
presentations of neurologic
disease, should help to
detect parasitic infections
of the central nervous
system.
OTHER PARASITIC INFECTIONS THAT MAY AFFECT THE HUMAN
NERVOUS SYSTEM
A variety of parasitic infections may affect the human CNS less frequently.
Epidemiologic suspicion based on country of origin or travel history, particularly
in the setting of atypical clinical presentations of neurologic disease, should alert
the clinician to consider parasitic infections of the CNS. Parasites that may cause
encephalitis, meningoencephalitis, and multiple brain abscesses include
free-living amoebas (Acanthamoeba species, Balamuthia mandrillaris, Naegleria
fowleri), Trypanosoma (sleeping sickness in African trypanosomiasis),
Angiostrongylus cantonensis (eosinophilic meningitis); Gnathostoma spinigerum
(gnathostomiasis), Strongyloides stercoralis (disseminated strongyloidiasis),
Trichinella spiralis (trichinosis), and Paragonimus (paragonimiasis). Focal
noncystic lesions can be found in Chagas disease (American trypanosomiasis);
toxocariasis (T. canis, Toxocara cati), paragonimiasis (Paragonimus species) or
sparganosis (Spirometra species), whereas cystic lesions occur in coenuriasis
(Taenia multiceps) and hydatid disease (Echinococcus granulosus). Hemorrhagic or
ischemic stroke can be caused by gnathostomiasis (G. spinigerum), disseminated
strongyloidiasis (S. stercoralis), and trichinosis (T. spiralis). Spinal disease can be
caused by toxocariasis and gnathostomiasis.

CONCLUSION
Parasitic infections affect the human CNS with relative frequency and should be
considered in the differential diagnosis of neurologic lesions, particularly in
individuals from endemic regions or those with a history of travel. Cerebral
malaria, toxoplasmosis, neurocysticercosis, and neuroschistosomiasis are among
the most common parasitic infections of the nervous system, but many other
diseases are caused by pathogenic parasites in the human host.

ACKNOWLEDGMENTS
The author is deeply grateful to Christina Coyle, MD (Einstein Medical College,
NY); Jose Vidal, MD (Instituto de Infectologia Emilio Ribas, Sao Paulo); and
Jesus Abanto, MD; Carolina Andrade, MD; Carolina Guzman, MD; Sofia Sanchez,
MD; and Luz Toribio, MSc (Universidad Cayetano Heredia, Lima) for their help in
providing material and reviewing and organizing the literature and cases.

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